Synthesis and anti-cancer activity of bis-amino-phosphine ligand and its ruthenium(II) complexes

The development of both chemotherapeutic drug resistance as well as adverse side effects suggest that the current chemotherapeutic drugs remain ineffective in treating the various types of cancers. The development of new metallodrugs presenting anti-cancer activity is therefore needed. Ruthenium complexes have gained a great deal of interest due to their promising anti-tumour properties and reduced toxicity in vivo. This study highlighted the effective induction of cell death in a malignant melanoma cell by two novel bis-amino-phosphine ruthenium(II) complexes referred to as GA105 and GA113. The IC₅₀ concentrations were determined for both the complexes, the ligand and cisplatin, for comparison. Both complexes GA105 and GA113 displayed a high anti-cancer selectivity profile as they exhibited low IC₅₀ values of 6.72 µM and 8.76 µM respectively, with low toxicity towards a non-malignant human cell line. The IC₅₀ values obtained for both complexes were lower than that of cisplatin. The new complexes were more effective compared to the free ligand, GA103 (IC₅₀ = >20 µM). Morphological studies on treated cells induced apoptotic features, which with further studies could indicate an intrinsic cell death pathway. Additionally, flow cytometric analysis revealed that the mode of cell death of complex GA113 was apoptosis. The outcomes herein give further insight into the potential use of selected Ru(II) complexes as alternative chemotherapeutic drugs in the future.     

CVII. Total synthesis of the structural gene for an alanine transfer ribonucleic acid from yeast. Synthesis of a dodecadeoxynucleotide and a hexadeoxynucleotide corresponding to the nucleotide sequence 1 to 12

A dodecadeoxynucleotide having the sequence, d-T-G-G-T-G-G-A-C-G-A-G-T, and a hexanucleotide having the sequence, d-C-C-A-C-C-A, have been chemically synthesized. These compounds represent, respectively, the nucleotide sequence 1 to 12 of one strand and 1 to 6 of the complementary strand of the gene corresponding to yeast alanine transfer RNA. The synthesis of the dodecanucleotide started with the condensation of 5′-O-monomethoxytrityl thymidine (d-MMTr-T) with N-benzoyl-3′-O-acetyl deoxyguanosine 5′-phosphate (d-pg^BZ-OAc) to give the dinucleotide, d-MMTr-TpG^BZ. Successive condensations of suitability protected mononuoleotides with the 3′-hydroxyl end of the growing chain gave the protected heptanucleotide, d-MMTr-TpG^BZpG^BZpTpG^BZpG^BZpA^BZ. The protected heptanucleotide was then condensed with the dinucleotide, d-pC^ANpG^BZ-OAc, to give the nonanucleotide, d-MMTr-TpG^BZpG^BZpTpG^BZpG^BZpA^BZpC^ANpG^BZ. Condensation of the nonanucleotide with the protected trinucleotide, d-pA^BZpG^BZpT-OAc, gave the protected dodecanucleotide, d-MMTr-TpG^BZpG^BZpTpG^BZpG^BZ-pA^BZpC^ANpGr^BZpA^BZpG^BZpT. The condensing agents used were dicyclohexylcarbodiimide, tri-isopropylbenzenesulfonyl chloride and mesitylenesulfonyl chloride. After removal of the protecting groups, the completely deprotected dodecanucleotide was further purified by anion-exchange chromatography in the presence of 7 M-urea. The steps involved in the synthesis of the hexanucleotide were: the condensation, of 5′-O-cyanoethyl phosphate of N₍₄₎-anisoyl deoxycytidylyl-(3′ → 5′)MN₍₄₎aniaoyl deoxycytidine, d-CEpC^AnpC^An, with d-pA^BZ-OAc to give the protected trinucleotide, d-pC^AnpC^AnpA^BZ, and the condensation of cyanoethyl derivative of the trinucleotide (d-CEpC^AnpC^AnpA^BZ) with the trinucleotide, d-pC^AnpC^AnpA^BZ-OAc, to give the protected hexanucleotide, d-pC^AnpC^AnpA^BZpC^AnpC^AnpA^BZ. After removal of the N-protecting groups the 5′-phosphate group was removed by treatment with bacterial alkaline phosphatase and the hexanucleotide, d-C-C-A-C-C-A, was isolated by paper chromatography. The yields varied between 20 and 80% at different steps.     

CVI. Total synthesis of the structural gene for an alanine transfer ribonucleic acid from yeast. Synthesis of two nonanucleotides and a heptanucleotide corresponding to nucleotide sequences 22 to 30, 41 to 49 and 28 to 34

Two nonadeoxynucleotides with the sequences, d-C-T-A-A-G-G-G-A-G (nonanucleotide-I) and d-T-C-T-C-C-G-G-T-T (nonanucleotide-II), and a heptadeoxynucleotide having the sequence, d-A-G-A-G-T-C-T, have been chemically synthesized. These polynucleotides represent, respectively, the nucleotide sequences 22 to 30, 41 to 49, and 28 to 34 of the gene for yeast alanine transfer RNA (Fig. 1). The synthetic steps used in the synthesis of the nonanucleotide-I were: the condensation of the protected nucleoside, d-MMTr-C^An, with the protected nucleotide, d-pT-OAc, to give the dinucleotide, d-MMTr-C^AnpT; the condensation of the dinucleotide with d-pA^Bz-OAc to give the trinucleotide, d-MMTr-C^AnpTpA^Bz; the condensation of the latter with the dinucleotide, d-pA^BzpG^1B-OAc, to give the pentanucleotide, d-MMTr-C^AnpTpA^BzpA^BzpG^1B; the condensation of this pentanucleotide with d-pG^1BpG^1B-OAc to give the protected heptanucleotide, d-MMTr-C^AnpTpA^BzpA^BzpG^1BpG^1BpG^1B, and finally, the condensation of this heptanucleotide with the dinucleotide, d-pA^BzpG^1B-OAc, to give the protected nonanucleotide, d-MMTr-C^AnpTpA^BzpA^BzpG^1BpG^1BpG^1BpA^BzpG^1B. The steps used in the synthesis of the nonanucleotide-II were: the condensation of d-MMTr-T with the tetranucleotide, d-pC^AnpTpC^AnpC^An-OAc, to give the pentanucleotide, d-MMTr-TpC^AnpTpC^AnpC^An; the condensation of the latter with the dinucleotide, d-pG^1BpG^1B-OAc, to give the heptanucleotide, d-MMTr-TpC^An-pTpC^AnpC^AnpG^1BpG^1B, and finally, the condensation of the heptanucleotide with the dinucleotide, d-pTpT-OAc, to give the protected deoxynonanucleotide, d-MMTr-TpC^AnpTpC^AnpC^AnpG^1BpG^1BpTpT. For the synthesis of the heptanucleotide, A-G-A-G-T-C-T, the 5′-monocyanoethyl tetranucleotide, d-CEpA^Bz-pG^1BpA^BzpG^1B, was condensed with the trinucleotide, d-pTpC^AnpT-OAc, to give the protected heptanucleotide, d-pA^BzpG^1BpA^BzpG^1BpTpC^AnpT. After removal of the N-protecting groups, the completely deprotected nonanucleotides, as well as the intermediate oligonucleotides and the heptanucleotide, d-A-G-A-G-T-C-T, were purified further by a combination of paper and column chromatography.     

Properties of homo- and heteronuclear mixed biscarbene complexes with conjugated bithiophene units

The syntheses and structures of homo- and heteronuclear biscarbene complexes with bithiophene spacers were investigated. The complexes were synthesized by lithiation of bithiophene followed by metallation using combinations of the metal precursors MnMeCp(CO)₃, W(CO)₆, Mo(CO)₆ and Cr(CO)₆, after which the reaction was quenched with triethyloxonium tetrafluoroborate. This classical Fischer method yielded monocarbene complexes, [ML_nC(OEt)C₄H₂S-C₄H₃S], ([ML_n] = Cr(CO)₅1a, W(CO)₅2a or MnMeCp(CO)₂3a), homonuclear biscarbene complexes, [ML_nC(OEt)C₄H₂S-C₄H₂SC(OEt)ML_n], ([ML_n] = Cr(CO)₅1b, W(CO)₅2b or MnMeCp(CO)₂3b) and heteronuclear biscarbene complexes, [ML_nC(OEt)C₄H₂S-C₄H₂SC(OEt)M′L_n] (1d: [ML_n] = Cr(CO)₅ and [M′L_n] = W(CO)₅; 1e: [ML_n] = MnMeCp(CO)₂ and [M′L_n] = Cr(CO)₅; 1f: [ML_n] = Cr(CO)₅ and [M′] = Mo(CO)₅); 2d: [ML_n] = MnMeCp(CO)₂ and [M′L_n] = W(CO)₅; 3c: [ML_n] = MnMeCp(CO)₂ and [M′L_n] = Mo(CO)₅). Electron density calculations with the gaussian03 software package of 1e revealed a polar rod with the negative pole towards the chromium carbene side, whereas the biscarbenes 1d and 1b showed very little polarity. By-products resulting from activation of the carbene moieties in homonuclear biscarbene complexes included (i) ester-type complexes of the form [ML_nC(OEt)C₄H₂S-C₄H₂SC(O)OEt], ([ML_n] = Cr(CO)₅1c or W(CO)₅2c), formed in situ in the reaction of 1b and 2b, (ii) the organic bis-ester compound [EtOC(O)C₄H₂S-C₄H₂SC(O)OEt] 4, where both metal moieties had been substituted by oxygen and (iii) the carbon-carbon coupled dimeric bithienyl compound [C₄H₃S-C₄H₂SC(O)C(O)C₄H₂S-C₄H₃S] 5. By-products obtained from heteronuclear biscarbene reactions contain the former diketo compound (or a derivative) as spacer between two metal carbonyl fragments and have the general formula [ML_nC(OEt)C₄H₂S-C₄H₂SCR-CR′C₄H₂S-C₄H₂SC(OEt)ML_n] (5a: [M] = Cr(CO)₅, R = OH, R′ = OEt; 5b: [M] = W(CO)₅, R = R′ = O; 5c: [M] = Mo(CO)₅, R = R′ = O). Reaction of 1d, 1e and 1f with hex-3-yne resulted in the formation of benzannulated products 6a, 6b and 6c. All novel complexes were fully characterized using various spectroscopic techniques. The crystal structures of 1b, 2a and 5 are reported.     

Antimicrobial effects of N-benzyloxycarbonyl-S-(2,4-dinitrophenyl) glutathione diesters against chloroquinine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum

N-Benzyloxycarbony-S-(2,4-dinitrophenyl)glutathione diesters have been investigated for antimalarial activity against chloroquinine sensitive (NF54) and resistant (K1) strains of P. falciparum. Both strains appear equally susceptible to inhibition by compounds 1–4, with an IC₅₀ ∼ 4.92–6.97 μM, consistent with the target of these compounds being the PfMRP transporter. Against the NF54 strain, diester derivatives containing ethyl side chains showed lower in vitro activity than those with methyl side chains 1–4, IC₅₀ ∼ 5.7–6.97 μM with the exception of compound 5 (IC₅₀ > 25 μM). The cytotoxicity of compounds with log P ∼ 3.9–5.8 were lower against the murine L6 cell line than compounds with a higher log P > 5.8 that were toxic. Overall the cytotoxicity of compounds 1–7 were lower against KB cells than against the L6 cell line with the exception of compound 4, which showed a higher relative toxicity.     

Synthesis,antitumor testing and molecular modeling study of some new 6-substituted amido,azo or thioureido-quinazolin-4(3H)-ones

A new series of 6-substituted amido, azo or thioureido-quinazolin-4(3H)-one was synthesized and tested for their in-vitro antitumor activity. Compounds 21, 53 and 60 showed broad spectrum antitumor activity with average IC₅₀ values of 6.7, 7.6 and 9.1 μM, respectively compared with methotrexate (1, IC₅₀ 19.26 μM). As an attempt to reveal the mechanism of the antitumor potency, cell cycle analysis and DHFR inhibition were performed. Compounds 59 and 61 induced their cytotoxicity in Hela (IC₅₀ 10.6 μM) and HCT-116 (IC₅₀ 15.5 μM) cell lines, respectively through Pre-G1 apoptosis, inhibiting cell growth at G2-M phase. Compounds 29, 33, 59 and 61 showed DHFR inhibitory potency at IC₅₀ 0.2, 0.2, 0.3 and 0.3 μM, respectively. The active DHFR inhibitors showed high affinity binding toward the amino acid residues Thr56, Ser59 and Ser118. The active compounds obeyed Lipinski’s rule of five and could be used as template model for further optimization.     

Bis-coumarins; non-cytotoxic selective urease inhibitors and antiglycation agents

The current study is concerned with the identification of lead molecules based on the bis-coumarin scaffold having selective urease inhibitory and antiglycation activities. For that purpose, bis-coumarins (1-44) were synthesized and structurally characterized by different spectroscopic techniques. Eight derivatives 4, 8-10, 14, 17, 34, and 40 demonstrated urease inhibition in the range of IC₅₀ = 4.4 ± 0.21–115.6 ± 2.13 μM, as compared to standard thiourea (IC₅₀ = 21.3 ± 1.3 μM). Especially, compound 17 (IC₅₀ = 4.4 ± 0.21 μM) was found to be five-fold more potent than the standard. Kinetic studies were also performed on compound 17 in order to identify the mechanism of inhibition. Kinetic studies revealed that compound 17 is a competitive inhibitor. Antiglycation activity was evaluated using glycation of bovine serum albumin by methylglyoxal in vitro. Compounds 2, 11-13, 16, 17, 19–22, 35, 37, and 42 showed good to moderate antiglycation activities with IC₅₀ values of 333.63–919.72 μM, as compared to the standard rutin (IC₅₀ = 294.46 ± 1.5 μM). Results of both assays showed that the compounds with urease inhibitory activity did not show any antiglycation potential, and vice versa. Only compound 17 showed dual inhibition potential. All compounds were also evaluated for cytotoxicity. Compounds 17, 19, and 37 showed a weak toxicity towards 3 T3 mouse fibroblast cell line. All other compounds were found to be non-cytotoxic. Urease inhibition is an approach to treat infections caused by ureolytic bacteria whereas inhibition of glycation of proteins is a strategy to avoid late diabetic complications. Therefore, these compounds may serve as leads for further research.     

Highly and Broad-Spectrum In Vitro Antitumor Active cis-Dichloridoplatinum(II) Complexes with 7-Azaindoles

The cis-[PtCl₂(naza)₂] complexes (1–3) containing monosubstituted 7-azaindole halogeno-derivatives (naza), showed significantly higher activity than cisplatin towards ovarian carcinoma A2780, its cisplatin-resistant variant A2780R, osteosarcoma HOS, breast carcinoma MCF7 and cervix carcinoma HeLa cell lines, with the IC₅₀ values of 3.8, 3.5, 4.5, 2.7, and 9.2 μM, respectively, obtained for the most active complex 3. As for 4 and 5 having disubstituted 7-azaindoles in their molecule, the significant cytotoxicity was detected only for 4 against A2780 (IC₅₀ = 4.8 μM), A2780R (IC₅₀ = 3.8 μM) and HOS (IC₅₀ = 4.3 μM), while 5 was evaluated as having only moderate antiproliferative effect against the mentioned cancer cell lines with IC₅₀ = 33.4, 24.7 and 46.7 μM, respectively. All the studied complexes 1–5 effectively avoided the acquired resistance of ovarian carcinoma cell line. On the other hand, the complexes did not reveal any inhibition activity on the purified 20S proteasome from the A2780 cells. The representative complexes 3 and 5 showed low ability to be hydrolysed, but their stability was markedly lowered in the presence of physiological sulphur-containing biomolecule glutathione (GSH), as proved by the ¹H NMR spectroscopy and mass spectrometry studies. A rate of interaction of the studied complexes with GSH was affected by an addition of another mechanistically relevant biomolecule guanosine monophosphate. The differences in interactions of 3 and 5 with GSH correlate well with their different cytotoxicity profiles.     

Synthesis,toxicity and antitumor activity of cobalt carbonyl complexes targeting hepatocellular carcinoma

Based on our previous research, a series of targeting hepatocellular carcinoma complexes, [R-Glycyrrhetinic acid-CH₂C₂H-[Co₂(CO)₆] (R = H, 1; R = NSAIDs-COOH, 2–4; R = Aromatic acid, 5–7; R = Amino acid, 8–10), were synthesized. The test showed they are slow CO releasers. Using HeLa, A549, HT-29, SMMC7721 and HepG2 cells as models, their activities against tumor cell proliferation were firstly evaluated. The resulting data show all the complexes displayed a good anti-proliferation activity against the HepG2 and SMMC-7721 liver cancer cells, and their IC₅₀ values were in the range of 10.07–66.06 µM; compared with cis-platin (DDP), their activities were comparable or even better under the same condition. Among them, complexes 3, 4, 6 and 9 exhibited higher anti-proliferation activities against HepG2 and SMMC-7721 cell lines than the other cell lines. To confirm further these complexes have selectivity to the liver cells, the uptakes of complexes 3, 4, 6 and 9 by HepG2, HT-29, A549 and SMMC7721 cell lines were studied. The results show the cell uptake rates of the complexes by HepG2 cells and SMMC7721 cells were much greater than by other cells under the same condition. In following tests, the tested complexes displayed higher activities in inhibiting NF-kB, COX-2 and iNOS; and they induced HepG2 cells apoptosis by mitochondrial pathway, which assessed by staining with different fluorescent reagent DAPI, PI, Mito-Tracker Green and DCFH-DA. Meanwhile, the tested complexes up-regulated the expression levels of caspase-3 and Bax, down-regulated the Bcl-2 expression. In addition, they had no effect on zebrafish embryo survival, embryo hatching, embryonic movement, zebrafish malformation and zebrafish movement at below 0.5 µM. This suggests the complexes are potential candidates to be used in clinic for liver cancers.     

Two new cytotoxic eudesmane sesquiterpenoids from Artemisia anomala

Two new eudesmane sesquiterpenoids artanoate (1) and eudesmanomolide (2) were isolated from the aerial parts of Artemisia anomala S. Moore. Their structures were elucidated as methyl (4R, 5S, 6S, 7S, 10R)-1-oxo-4, 6-dihydroxy-eudesma-2, 11 (13)-dien-12-oate (1) and (1R, 5R, 6R, 10R)-3, 13-diacetoxy-1-hydroxy-3, 7(11)-diene-12, 6-olide (2) on the basis of extensive spectroscopic analyses. Compound 1 showed cytotoxicity against HCT-8 cell lines with IC₅₀ value of 9.13 μM, and compound 2 exhibited inhibitory activities against HCT-8 and A549 cell lines with IC₅₀ values of 3.76 and 5.49 μM, respectively.     

Design,synthesis, DNA-binding affinity,cytotoxicity, apoptosis,and cell cycle arrest of Ru(II) polypyridyl complexes

A novel polypyridyl ligand CNPFIP (CNPFIP = 2-(5(4-chloro-2-nitrophenyl)furan-2-yl)-1H-imidazo[4,5f][1,10]phenanthroline) and its mononuclear Ru(II) polypyridyl complexes of [Ru(phen)₂CNPFIP]²⁺(1) (phen = 1,10-phenanthroline), [Ru(bpy)₂CNPFIP]²⁺(2) (bpy = 2,2′-bipyridine), and [Ru(dmb)₂CNPFIP]²⁺(3) (dmb = 4,4′-dimethyl-2,2′-bipyridine) have been synthesized successfully and characterized thoroughly by elemental analysis, UV/Vis, IR, NMR, and ESI-MS. The interaction of the Ru(II) complexes with calf thymus DNA (CT-DNA) was investigated by absorption titration, fluorescence, viscosity measurements. The experimental results suggest that three complexes bind to CT-DNA through an intercalative mode and the DNA-binding affinity of complex 1 is greater than that of complexes 2 and 3. The photocleavage of plasmid pBR322 DNA by ruthenium complexes 1, 2, and 3 was investigated. We have also tested three complexes for their antimicrobial activity against Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) bacteria. The in vitro cytotoxicity of these complexes was evaluated by MTT assay, and complex 1 shows higher cytotoxicity than 2 and 3 on HeLa cells. The induced apoptosis and cell cycle arrest of HeLa cells were investigated by flow cytometry for 24 h. The molecular docking of ruthenium complexes 1, 2, and 3 with the active site pocket residues of human DNA TOP1 was performed using LibDock.     

Synthesis,structures and urease inhibitory activity of cobalt(III) complexes with Schiff bases

A series of new cobalt(III) complexes were prepared. They are [CoL¹(py)₃]·NO₃ (1), [CoL²(bipy)(N₃)]·CH₃OH (2), [CoL³(HL³)(N₃)]·NO₃ (3), and [CoL⁴(MeOH)(N₃)] (4), where L¹, L², L³ and L⁴ are the deprotonated form of N′-(2-hydroxy-5-methoxybenzylidene)-3-methylbenzohydrazide, N′-(2-hydroxybenzylidene)-3-hydroxylbenzohydrazide, 2-[(2-dimethylaminoethylimino)methyl]-4-methylphenol, and N,N′-bis(5-methylsalicylidene)-o-phenylenediamine, respectively, py is pyridine, and bipy is 2,2′-bipyridine. The complexes were characterized by infrared and UV–Vis spectra, and single crystal X-ray diffraction. The Co atoms in the complexes are in octahedral coordination. Complexes 1 and 4 show effective urease inhibitory activities, with IC₅₀ values of 4.27 and 0.35 μmol L⁻¹, respectively. Complex 2 has medium activity against urease, with IC₅₀ value of 68.7 μmol L⁻¹. While complex 3 has no activity against urease. Molecular docking study of the complexes with Helicobacter pylori urease was performed.     

Trans-cis-cis-[RuCl2(DMSO)2(2-amino-5-methyl-thiazole)2], (PMRu52), a novel ruthenium(II) compound acting as a strong inhibitor of cathepsin B

A novel ruthenium(II) compound, trans-cis-cis-[Ru(II)Cl₂(DMSO)₂(2-amino-5-methyl-thiazole)₂], (I), PMRu52 hereafter, that may be obtained from the previously described (cis and trans)-[Ru(II)Cl₂(DMSO)₄] complexes, was designed, synthesized and characterised. The single crystal X-ray structure shows a roughly regular octahedral environment for the ruthenium(II) center with the two chloride ligands in trans and the other two pairs of identical ligands in cis. The behaviour of PMRu52 in phosphate buffer, at pH = 7.4, was characterised spectroscopically as well as its interactions with a few representative biomolecules. Tight ruthenium binding to serum albumin was established by joint use of spectroscopic and separation methods. Afterward, the reactions of PMRu52 with the model proteins ubiquitin and cytochrome c were monitored through electrospray ionisation mass spectrometry (ESI-MS) methods: the formation of metallodrug-protein adducts was documented in detail and the fragmentation patterns of PMRu52 were defined. Finally, the ability of PMRu52 to affect the activity of cathepsin B, a well known cysteine protease, was evaluated in vitro and a pronounced enzyme inhibition highlighted, with an IC₅₀ value of 5.5 μM. This latter finding is of particular interest as cathepsin B constitutes an attractive “druggable” target for cancer, rheumatoid arthritis and other important diseases.     

Near infrared photoluminescence of ytterbium(III) complexes from tripodal ligands with different coordination conformations

Fourteen ytterbium(III) complexes of the tripodal ligands triRNTB (N-substituted tris(benzimidazol-2-ylmethyl)amine) have been prepared and characterized by elemental analysis (EA), infrared spectra (IR), electrospray ionization mass spectrometry (ESI-MS) and single-crystal diffraction analysis. Their coordination conformations can be divided into three different types due to the introduction of secondary ligands or counter anions, i.e. ML₂, , and MLA₃ types, therefore resulting in different coordination symmetry on the central Yb(III) ions. Accordingly, the near infrared photoluminescence and photophysical properties of the complexes show contrasting results in peak splitting behavior, lifetime, and quantum efficiency, among which the ML₂ type displaying the most complicated splitting, the shortest lifetime and the smallest quantum efficiency.     

Transition metal complexes (M = Cu, Ni and Mn) of Schiff-base ligands: Syntheses, crystal structures, and inhibitory bioactivities against urease and xanthine oxidase

Six new transition metal complexes (M = Cu(II), Ni(II) and Mn(III)) of tridentate (H₂L¹, HL²) and/or bidentate (HL³, HL⁴) Schiff-base ligands, obtained from the condensation of salicylaldehyde with glycine, N-(2-aminoethyl)morpholine, 4-(2-aminoethyl)phenylic acid and 4-(2-aminoethyl)benzsulfamide, respectively, were synthesized and structurally determined by single-crystal X-ray analysis. Complexes 1-6 were evaluated for their effect on the jack bean urease and xanthine oxidase (XO). Copper(II) complexes 1-3 (IC₅₀ = 0.43-2.25 μM) showed potent inhibitory activity against jack bean urease, comparable with acetohydroxamicacid (IC₅₀ = 42.12 μM), which is a positive reference. And these copper(II) complexes (IC₅₀ = 10.26-15.82 μM) also exhibited strong ability to inhibit activity of XO, comparable to allopurinol (IC₅₀ = 10.37 μM), which was used as a positive reference. Nickel(II) and manganese(III) complexes 4-6 showed weak inhibitory activity to jack bean urease (IC₅₀ = 4.36-8.25 μM) and no ability to inhibit XO (IC₅₀ > 100 μM).     

Synthesis,and In Vitro and In Silico α-Glucosidase Inhibitory Studies of 5-Chloro-2-Aryl Benzo[d]thiazoles

Twenty-five derivatives of 5-chloro-2-aryl benzo[d]thiazole (1–25) were synthesized and evaluated for their α-glucosidase (S. cerevisiae EC 3.2.1.20) inhibitory activity in vitro. Among them eight compounds showed potent activity with IC₅₀ values between 22.1 ± 0.9 and 136.2 ± 5.7 μM, when compared with standard acarbose (IC₅₀ = 840 ± 1.73 μM). The most potent compounds 4, 9, and 10 showed IC₅₀ values in the range of 22.1 ± 0.9 to 25.6 ± 1.5 μM. Compounds 2, 5, 11, and 19 showed IC₅₀ values within the range of 40.2 ± 0.5 to 60.9 ± 2.0 μM. Compounds 1 and 3 were also found to be good inhibitors with IC₅₀ values 136.2 ± 5.7 and 104.8 ± 9.9 μM, respectively. Their activities were compared with α-glucosidase inhibitor drug acarbose (standard) (IC₅₀ = 840 ± 1.73 μM). The remaining compounds were inactive. Structure-activity relationships (SAR) have also been established. Kinetics studies indicated compounds 2, 3, 10, 19, and 25 to be non-competitive, while 1, 5, 9, and 11 as competitive inhibitors of α-glucosidase enzyme. All the active compounds (1–5, 9–11, and 19) were also found to be non-cytotoxic, in comparison to the standard drug i.e., doxorubicin (IC₅₀ = 0.80 ± 0.12 μM) in MTT assay. Furthermore, molecular interactions of active compounds with the enzyme binding sites were predicted through molecular modeling studies.     

Novel DNA intercalators without basic side chains as efficient antitumor agents: Design,synthesis and evaluation of benzo-[c,d]-indol-malononitrile derivatives

Several 2-(substituted benzo[c,d]indol-2(1H)-ylidene)malononitriles have been designed and synthesized. Their DNA binding, antitumor and DNA damaging properties were evaluated. All the compounds exhibited efficient antitumor activities with preference to be against the tumor cell line 7721 rather than the tumor cell line MCF-7. Compound 1f could intercalate into DNA entirely presumably by the good conjugation of carbonyl group with benzo[c,d]indol moiety. What’s more, 1f exhibited potent toxicity against MCF-7 cells with IC₅₀ at 0.003 μM and against 7721 cells at 0.115 μM, respectively.     

Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines

In an effort to establish new candidates with enhanced anticancer activity of 5-hydroxy-7-methyl-1,4-naphthoquinone scaffold (7-methyljuglone) previously isolated from the root extract of Euclea natalensis, a series of 7-methyljuglone derivatives have been synthesized and assessed for cytotoxicity on selected human cancer lines. These compounds were screened in vitro for anticancer activity on MCF-7, HeLa, SNO and DU145 human cancer cell lines by MTT assay. Most of them exhibited significant toxicity on cancer cell lines with lower IC₅₀ values. The most potent derivative (19) exhibited the toxicity on HeLa and DU145 cell lines with IC₅₀ value of 5.3 and 6.8 μM followed by compound (5) with IC₅₀ value of 10.1 and 9.3 μM, respectively. Structure–activity relationship reveals that the fluoro substituents at position C-8 while hydroxyl substituents at C-2 and C-5 positions played an important role in toxicity.     

Synthesis and in vitro anticancer evaluation of some fused indazoles,quinazolines and quinolines as potential EGFR inhibitors

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC₅₀ values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC₅₀ values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC₅₀ value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC₅₀ = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC₅₀ = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.     

Synthesis,anticancer assessment on human breast,liver and colon carcinoma cell lines and molecular modeling study using novel pyrazolo[4,3-c]pyridine derivatives

The key intermediate 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) is considered as a precursor for some novel pyrazolo[4,3-c]pyridines 4a-c, arylhydrazopyrazolo[4,3-c]pyridines 8a-e, pyrazolo[4,5,1-ij][1,6]naphthyridines 11a-e and pyrido[4′,3′:3,4]pyrazolo[1,5-a]-pyrimidines 15a-d through Knovenegal condensation, coupling reaction and Michael addition. Some of the newly synthesized pyrazolo[4,3-c]pyridine derivatives were investigated for anticancer activity. The results of the cytotoxic activity revealed that compound 6b was the most active compound against the breast and liver carcinoma cell lines which gives IC₅₀ values of 1.937 and 3.695 µg/mL, respectively compared to reference drug (doxorubicin) with IC₅₀ values of 2.527 and 4.749 µg/ml, respectively. Moreover, compound 6c was potent compound against the colon carcinoma cell line which gives the value of IC₅₀ = 2.914 µg/ml compared to doxorubicin with IC₅₀ value of 3.641 µg/ml. Some selected of the novel synthesized compounds were docked inside the active site of ERK2 enzyme and were found display a suitable binding with the active site amino acids according to their bond lengths, angles and conformational energy.